The frontal lobes reach their highest development in man, in whom they are thought to provide a sophisticated nueral system for the analysis of options and outcomes, organization of behavior toward future goals, and for the regulation of socially and culturally appropriate behavior. The ultimate goal of this research program is to understand the frontal lobes and their contribution to higher-order cognitive functions by detailed experimental study of its anatomy, physiology, neurochemistry and behavioral expression in nonhuman primates. This program has evolved over a period of more than 15 years to its present focus on: [1] anatomical organization with particular emphasis on microstructural analysis of the topographic, laminar and columnar organization, and degree of collateralization of prefrontal cortical connections using advanced morphological techniques including autoradiography, horseradish peroxidase, fluorescent dyes, fluorescent histochemistry, immunohistochemistry, electron microscopy, and receptor autoradiography; [2] functional analysis of prefrontal cortex using a combination of behavioral analysis, 2-deoxyglucose autoradiography for mapping metabolic activity and electrophysiology to elucidate the cellular basis of prefrontal function; [3] psychopharmacological and comparative studies to study the role of monoamines in cognitive functions and to establish a link between studies of prefrontal corte in nonhuman primates and in man, e.g., by analysis of behaviors common to both species; and also assessment and drug treatment of cognitive deficits in aged animals with endogenous depletion of prefrontal catecholamines; and [4] studies of development and plasticity of prefrontal neural connectivity and its relation to recovery of function after early brain injury. All experiments are conducted on rhesus monkeys whose prefrontal corte is well developed and who are unexcelled as laboratory animal models of human learning and memory. This research strategy is broadly multidisciplinary and each major project intersects with every other, both conceptually and technically. The proposed studies should enrich our understanding of the neural circuits and cellular basis of cognitive functions and their breakdown in mental disease.